Block 1 Transplant Pathology

Question 1

Isograft, allograft, and xenograft

Answer 1

Iso: genetically identical individuals
Allo: different members of same species
Xeno: members of different species

Question 2

Major targets of immune response in rejection

Answer 2

MHC/HLA molecules (allo-MHC)

Question 3

Products of HLA genes & location

Answer 3

On chr 6
Class 1: *A, *B, C
Class 2: *DR, DQ
Class 3: complement components, TNF, lymphotoxin
* = most important in immune rejection

Question 4

Complications to sibling-sibling transplant

Answer 4

Mendelian inheritance of HLA haplotypes = children may have very different HLA profiles

Question 5

Direct pathway of immune recognition of allograft

Answer 5

Host T cells recognize intact allo-MHC on donor cell surface -> CD4 (activate MF) and CD8 to lyse
*Dominant pathway involved in early illumine response

Question 6

Indirect pathway of immune recognition of allograft

Answer 6

T cells recognize processed alloantigen presented by own APCs -> CD4 -> activate MF and B cells -> Abs to allo-Ag
*Possibly in chronic or late acute rejection

Question 7

Main location of attack in immune rejection

Answer 7

Endothelium/ epithelium of renal tubules because high density HLA antigen

Question 8

Main cells involved in T-cell mediated allograft rejection

Answer 8

Cytotoxic T cells, Th cells, MFs

Question 9

Main factors involved in Ab-mediated allograft rejection

Answer 9

Allo-Abs against graft MHC, other allo-Ag, complement activation, recruitment leukos, ADCC

Question 10

Timeline and mechanism of hyperacute, acute and chronic rejection

Answer 10

HA: minutes-hours, preformed anti-donor Abs
A: days-weeks, activation alloreactive T cells (cell and Ab-mediated)
C: months-years, slow cellular response (cell and Ab-mediated), response of organ to injury, unknown causes

Question 11

Causes of preformed Ab in hyperacute rejection, frequency, & treatment

Answer 11

Hx transfusions, multiple pregnancies, second transplant
*Rare because we know to test for this before transplant
Life-threatening: remove organ quickly

Question 12

Main tissue outcomes in HA rejection

Answer 12

Ex: kidney mottled, cyanotic, flaccid
Deposition of Ig and complement
Endothelial injury, fibrin thrombi
Accumulation neutrophils (later)

Question 13

Causes of organ damage in acute rejection

Answer 13

Mononuclear inflam cell infiltrate (interstitial) of mostly T lymphs
Ex: kidney inflammation tubules = tubulitis; and inflam vessels = endothelitis

Question 14

Causes of organ damage in chronic rejection

Answer 14

Interstitial inflam
Ex: kidney fibrosis and tubular atrophy (IFTA), global glomerulosclerosis, graft arteriosclerosis d/t extended intima (chronic transplant arteriopathy)

Question 15

Ab-mediated rejection mechanism & pathology

Answer 15

D/t presence of circulation donor-specific Abs (DSA)
Tubular injury, mild inflam, capillaritis, thrombosis, vasculitis; CD4 deposits in peritubular caps d/t Ab-Ag complement activation

Question 16

Preventing graft rejection methods

Answer 16

Screening for preformed HLA Abs

Cross-matching (mix recipient serum with donor lymphs - look for lysis)

Question 17

Examples of organs where cross-matching is more and less important

Answer 17

Liver/heart: HLA less important than matching organ size

BM: HLA matching more important, to prevent GVHD

Question 18

Cyclosporine

Answer 18

Immunosuppressive agent that blocks activation of TFs for cytokine genes (IL-2)

Question 19

Azathioprine

Answer 19

Imm supp drug that inhibits leuko dev from BM precursors

Question 20

Steroids

Answer 20

Imm supp drug because anti-inflam

Question 21

Rapamycin, mycophenolate mofetil

Answer 21

Imm supp drug bc inhibit T cell proliferation

Question 22

Examples of immunosuppressive monoclonal antibodies

Answer 22

Anti-T-cell (anti-CD3), anti-IL-2-R (anti-CD25)

Question 23

Belatacept

Answer 23

Imm supp drug by blockade of co-stim signals from DCs (blocks B7)

Question 24

B-cell depleting imm supp drug

Answer 24

Anti-CD20 Ab: rituximab

Question 25

Plasmapheresis as imm supp therapy

Answer 25

Removes antibodies

Question 26

Complications of immunosuppressive drugs

Answer 26

Toxicity

Immunodeficiency & opportunistic infxns

Question 27

Examples of opportunistic infections in immunosuppressed

Answer 27

CMV, Kaposi sarcoma, fungal infections
EBV -> posttransplant lymphoproliferative disorder (PTLD)
Papillomavirus -> induced squamous cell carcinoma
BK polyomavirus -> nephropathy

Question 28

Stem cell transplant: sources of stem cells, disorders treated, problems

Answer 28

BM, mobilizer peripheral blood stem cells, umbilical cord blood
Hematologic maligs, severe aplastic anemia, thalassemias, severe cong immuno def, certain non-heme cx like neuroblastoma
GVHD & immunodef

Question 29

GVHD general characteristics

Answer 29

Acute or chronic, rarely seen in solid organ transplant

Immunologically competent cells or precursors transplanted into imm crippled recipient & attack the host allo-Ags

Question 30

Acute GVHD timeline, symptoms, pathogenesis

Answer 30

Days-weeks after allogeneic BM transplant
Generalized rash, jaundice, gut ulceration, bloody diarrhea; involves immune sys, epithelium of skin, liver, intestines
Direct CD8 cytotoxicity, cytokines

Question 31

Chronic GVHD timeline, symptoms, pathogenesis

Answer 31

After acute or insidiously
Extensive cutaneous injury, cholestatic jaundice, esophageal strictures, depletion lymphs
CD4-mediated
*Life threatening

Question 32

Preventing GVHD

Answer 32

HLA matching!!!!

Donor T-cell depletion

Question 33

Problems with donor T-cell depletion in GVHD prevention

Answer 33

Graft failure
T-cells: mediate GVHD, are required for sufficient engraftment, & role in elimination of leukemia cells (GVL phenomenon)